Spatio-temporal differences in the profile of murine brain expression of proinflammatory cytokines and indoleamine 2,3-dioxygenase in response to peripheral lipopolysaccharide administration

Abstract

The mechanisms underlying in vivo activation of indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme that mediates in the brain the induction of depressive-like behavior by peripheral innate immune system stimulation are still poorly understood. By monitoring how cytokines parallel IDO mRNA expression in the brain in response to intraperitoneal lipopolysaccharide injection in mice, we report a time-dependent induction of IDO expression in both the hippocampus and hypothalamus that was associated with a specific structure-dependent expression of proinflammatory cytokines, particularly interferon-gamma. This study suggests that different mechanisms regulate the activation of IDO by lipopolysaccharide in various brain structures.

Fig 1

(A) Temporal evolution of changes in body weight in response to i.p. saline or LPS. (B) Time course of lung IDO activity in response to LPS. Mice were injected i.p. with either saline or LPS (830 μg/kg) and IDO activity was assessed by the KYN/TRP ratio in lungs collected 2, 6, 12 or 24 h after injection. Data represent the means ± SEM (n= 6).The * symbol represented statistical differences between saline and LPS groups, **p<0.01; ***p<0.001. Bars labeled with different letters (a, b or c) are significantly different from each other (p<0.05). Note that the basal body weight did not differ between the two experimental groups (global mean and SEM).

Fig 2

Time course of IL-1β (A), TNFβ (B), IL-6 (C), and IFNγ (D) concentrations measured in plasma collected 2, 6, 12, or 24 h after LPS (830 μg/kg) or saline injection. Bars represented the means ± SEM (n= 6). The * symbol represented statistical differences between saline and LPS groups, *p<0.05; **p<0.01; ***p<0.001. Bars labeled with different letters (a, b or c) are significantly different from each other (p<0.05).

Fig 3

Effect of LPS on mRNA expression of IDO (A), IL-1β (B), TNFα (C), IL-6 (D) and IFNγ (E) in the hippocampus. Mice were injected i.p. with saline or LPS (830 μg/kg) and hippocampus were collected 2, 6, 12 or 24 h after injection. Data represented the means ± SEM (n= 6). The * symbol represented statistical differences between saline and LPS groups, *p<0.05; **p<0.01; ***p<0.001. Bars labeled with different letters (a, b or c) are significantly different from each other (p<0.05). nd = no detectable.

Fig 4

Effect of LPS on mRNA expression of IDO (A), IL-1β (B), TNFα (C), IL-6 (D) and IFNγ (E) in the hypothalamus. Mice were injected i.p. with saline or LPS (830 μg/kg) and hypothalamus were collected 2, 6, 12 or 24 h after injection. Data represented the means ± SEM (n= 6). The * symbol represented statistical differences between saline and LPS groups, *p<0.05; **p<0.01; ***p<0.001. Bars labeled with different letters (a, b or c) are significantly different from each other (p<0.05). nd = no detectable.